PROJECT SUMMARY/ABSTRACT Youth with neurofibromatosis type 1 (NF1) experience significant problems with social functioning that adversely impacts quality of life across the lifespan and often resemble the difficulties prominent in autism spectrum disorder (ASD). Studies examining the prevalence of ASD in NF1 reveal rates of significant ASD symptomatology of 40-63% and ASD diagnosis in 24.9% of youth with NF1. Few studies have attempted to identify the neurobiological risk factors for ASD symptomatology and diagnosis in youth with NF1. Establishing the neurobiological mechanisms associated with an ASD diagnosis in NF1 is important to developing therapies that target these underlying processes in youth with NF1 and ASD and reduce social impairments. The broad objectives of this proposal are to identify the neurobiological processes related to ASD diagnosis and symptomatology in NF by comparing relevant neurophysiological factors between four groups of thirty youth ages 8-12: 1) youth with both NF1 and ASD (NF1+ASD), 2) youth with NF1 only (NF1-ASD), 3) youth with ASD-I, and 4) typically developing (TD) youth. Neurobiological metrics of interest include auditory encoding latencies (M100 prolongations), neurotransmitter activity (GABA) and white matter integrity. Specific aims include 1) comparing the four groups on these measures of neurophysiological and neuroanatomical factors using magnetoencephalography (MEG), magnetic resonance spectroscopy and diffusion magnetic resonance imaging and 2) determining associations between neurophysiological measures and clinical/behavioral phenotypic markers of ASD in youth with NF1. We hypothesize similar neurophysiologic phenotypes in NF1+ASD and ASD-I compared to the NF1-ASD and TD groups, increased social and communication impairments in the NF1+ASD group, and differential associations in the NF1+ASD and NF1-ASD groups between neurophysiological and clinical/behavioral measures. The proposed study will recruit the two groups of youth with NF1 (NF1+ASD, NF1-ASD) from the Neurofibromatosis Program at The Children's Hospital of Philadelphia. Participants will complete an ASD diagnostic evaluation, neuropsychological testing and neuroimaging. The comparison groups will be drawn from an existing data set from another project (5R01DC008871). We expect to determine if disrupted auditory cortex neural activity (as evidenced by M100 latency delays), differential GABA and glutamate functioning, and reduced white matter integrity are associated with an increased risk for ASD diagnosis or ASD symptoms in youth with NF1. These findings will significantly advance our understanding of the underlying mechanisms of the ASD phenotype observed in youth with NF1 and will provide a foundation for research that informs direct treatments and delineates NF1 as a distinct subtype in the ASD continuum and advance our understanding of the broader ASD population.